Graves? disease (GD) is the most common cause of hyperthyroidism and is caused by stimulation of the thyroid-stimulating hormone receptor (TSHR) by thyroid receptor stimulating antibodies (TSAbs). Treatment of GD involves antithyroid medication therapy, radioactive iodine, and surgery. At the present, few alternative forms of therapy for GD are available or are in development. The ability to block TSHR action may also be of benefit to other conditions, including Graves; orbitopathy (GO) and differentiated thyroid cancer. Thus, there is considerable interest in developing novel treatments to block TSHR action. Recombinant adeno- associated virus (rAAV) therapy has been developed as a viral vector for gene therapy. Several of these clinical trials have taken place at the University of Florida (UF), which is a major center for the study of AAV- based gene therapy. Of the different rAAV that the serotypes that are available, rAAV8 is the preferred vector for vector-mediated immunotherapy studies in rodent models. Although vector-based immunotherapy has been proposed for infectious diseases, we such approaches that target antibody-mediated conditions are limited. In preliminary studies, we identified a commercially available monoclonal antibody that blocks TSAb and thyroid-stimulating hormone (TSH) action. We also developed a rAAV8 construct that expresses this functional antibody. Thus, we hypothesize that the rAAV9-TBAb vector we generated will target and block TSHR activation. In this Phase 1 STTR proposal, we will evaluate the utility of our new therapeutic in blocking TSH receptor activation. In SA 1, we will test the ability of our therapeutic to block the action of TSH in single dose and multidose studies. In SA 2, we will test the ability of our vector to block the activity of administered TSAbs and a validated murine model of GD. To achieve these goals, our team will include experts in thyroidology and rAAV biology and will involve collaborative efforts of the University of Florida and Medosome Biotec LLC. We anticipate that the discovery of this novel therapeutic approach to inhibit thyroid production and block TSAbs will be of considerable clinical importance and commercial potential.